The physiological role of titin in striated muscle

Horowits, Robert

doi:10.1007/bf02346660

Cited by 39 publications

(28 citation statements)

References 103 publications

(259 reference statements)

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“…Its elasticity lies specifically in the I-band region and contains two elements in series with different properties: the tandem immunoglobulin (Ig) and PEVK domains. 33 Different TTN isoforms contribute to differences in elasticity of different muscle types. 34 As exon 45 is located at the tandem Ig domains, aberrant inclusion of exon 45 in DM1 might lead to defective myofibril assembly and function.…”

Section: Potential Roles Of Novel Aberrant Splicing Events In Dm1mentioning

confidence: 99%

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

et al. 2012

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Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder in which abnormally expanded CTG repeats of DMPK sequestrate a splicing trans-factor MBNL1 and upregulate another splicing trans-factor CUGBP1. To identify a diverse array of aberrantly spliced genes, we performed the exon array analysis of DM1 muscles. We analyzed 72 exons by RT-PCR and found that 27 were aberrantly spliced, whereas 45 were not. Among these, 25 were novel and especially splicing aberrations of LDB3 exon 4 and TTN exon 45 were unique to DM1. Retrospective analysis revealed that four parameters efficiently detect aberrantly spliced exons: (i) the signal intensity is high; (ii) the ratio of probe sets with reliable signal intensities (that is, detection above background P-value ¼ 0.000) is high within a gene; (iii) the splice index (SI) is high; and (iv) SI is deviated from SIs of the other exons that can be estimated by calculating the deviation value (DV). Application of the four parameters gave rise to a sensitivity of 77.8% and a specificity of 95.6% in our data set. We propose that calculation of DV, which is unique to our analysis, is of particular importance in analyzing the exon array data. INTRODUCTIONAlternative splicing regulates developmental stage-specific and tissuespecific gene expressions and markedly expands the proteome diversity with a limited number of genes. High-throughput sequencing of total mRNAs expressed in cells has revealed that 98% or more of multiexon genes are alternatively spliced, 1 with an average of seven alternative splicing per multiexon gene. 2 Alternative splicing is achieved by exonic/intronic splicing enhancers/silencers (ESE, ISE, ESS, ISS) in combination with spatial and temporal expression of trans-acting splicing factors, such as serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins. 3,4 Aberrations of alternative splicing are mediated by either mutations disrupting splicing cis-elements or dysregulation of splicing trans-factors. 5,6 Myotonic dystrophy is an autosomal dominant multisystem disorder affecting the skeletal muscles, eye, heart, endocrine system and central nervous system. The clinical symptoms include muscle weakness and wasting, myotonia, cataract, insulin resistance, hypogonadism, cardiac conduction defects, frontal balding and intellectual

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Section: Potential Roles Of Novel Aberrant Splicing Events In Dm1mentioning

confidence: 99%

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

et al. 2012

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“…As the fiber lengthens, the filaments slide relative to each other. Titin binds both thick filaments and the Z-disk and is loaded and elongated as the sarcomere is extended (41,63). There is some evidence to suggest that members of the ankyrin repeat protein (ARP) family can be displaced by stretch from titin to the nucleus (64), where they form complexes with transcription factors YB-1 and p53 (64,65).…”

Section: Cellular Deformationmentioning

confidence: 99%

Mechanotransduction in skeletal muscle

Burkholder¹

2007

Front Biosci

110

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Mechanical signals are critical to the development and maintenance of skeletal muscle, but the mechanisms that convert these shape changes to biochemical signals is not known. When a deformation is imposed on a muscle, changes in cellular and molecular conformations link the mechanical forces with biochemical signals, and the close integration of mechanical signals with electrical, metabolic, and hormonal signaling may disguise the aspect of the response that is specific to the mechanical forces. The mechanically induced conformational change may directly activate downstream signaling and may trigger messenger systems to activate signaling indirectly. Major effectors of mechanotransduction include the ubiquitous mitogen activated protein kinase (MAP) and phosphatidylinositol-3' kinase (PI-3K), which have well described receptor dependent cascades, but the chain of events leading from mechanical stimulation to biochemical cascade is not clear. This review will discuss the mechanics of biological deformation, loading of cellular and molecular structures, and some of the principal signaling mechanisms associated with mechanotransduction. KeywordsSkeletal muscle; mechanotransduction; stretch INTRODUCTIONThe detection and response to physical forces is essential to all cells, but is particularly relevant to those that play a fundamentally mechanical role. The primordial nature of the cellular interaction with the physical world suggests that its control should be highly regulated and specific, and that the response should integrate many aspects of cellular physiology. Pathways involved in detecting and producing forces in muscle overlap those involved in detecting nutrient availability (1,2), intracellular energy status (3,4), and oxidative status (5,6). The signaling pathways modulated by force, insulin and insulin-like growth factor I (IGF-I)(7), adenosine monophosphate (AMP) dependent kinase (AMPK) (8), reactive oxygen species (ROS) (9), and prostaglandins (PG) (10) seem intractably intertwined.The adaptations of skeletal muscle to mechanical signals have been widely described, and the interested reader is referred to several recent reviews (11)(12)(13)(14). The physiological increase in force generating capacity associated with activity, and the increase in flexibility associated with stretch, were recognized in antiquity, but the mechanisms by which those changes manifest are still unclear. The present intention is to consider the shape changes and forces associated with mechanical signals and juxtapose them with observed changes in biochemical signaling to determine what might contribute to the cellular perception of mechanical signals.Careful consideration of the mechanical environment is the first step to sort out that labyrinth of signaling. When one considers mechanisms by which the mechanical environment can be NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sensed, it is common to think of "force" and "deformation" separately. Sometimes this distinction is legitimate, bu...

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“…The generally accepted view is that the elasticity of stri-ated muscle is largely determined by the giant protein titin, one of the major components of the sarcomere (see reviews by Trinick 1994Trinick , 1996Wang 1996;Maruyama 1997;Linke & Granzier 1998;Gautel et al 1999;Horowits 1999;Trinick & Tskhovrebova 1999;Linke 2000). Extensibility of titin in the I-band, and its relation to passive tension, was clearly demonstrated by in situ immunofluorescence and immuno-electron microscopy, and by mechanical measurements on fibres and myofibrils (Wang et al 1991(Wang et al , 1993Horowits 1992;Granzier et al 1996;Linke et al 1996;Trombitás et al 1998Trombitás et al , 2000.…”

Section: Muscle Elasticitymentioning

confidence: 99%

Role of titin in vertebrate striated muscle

Tskhovrebova

Trinick

2002

Phil. Trans. R. Soc. Lond. B

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Titin is a giant muscle protein with a molecular weight in the megaDalton range and a contour length of more than 1 m. Its size and location within the sarcomere structure determine its important role in the mechanism of muscle elasticity. According to the current consensus, elasticity stems directly from more than one type of spring-like behaviour of the I-band portion of the molecule. Starting from slack length, extension of the sarcomere first causes straightening of the molecule. Further extension then induces local unfolding of a unique sequence, the PEVK region, which is named due to the preponderance of these amino-acid residues. High speeds of extension and/or high forces are likely to lead to unfolding of the ␤-sandwich domains from which the molecule is mainly constructed. A release of tension leads to refolding and recoiling of the polypeptide.Here, we review the literature and present new experimental material related to the role of titin in muscle elasticity. In particular, we analyse the possible influence of the arrangement and environment of titin within the sarcomere structure on its extensible behaviour. We suggest that, due to the limited conformational space, elongation and compression of the molecule within the sarcomere occur in a more ordered way or with higher viscosity and higher forces than are observed in solution studies of the isolated protein.

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The physiological role of titin in striated muscle

Cited by 39 publications

References 103 publications

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

Mechanotransduction in skeletal muscle

Role of titin in vertebrate striated muscle

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